Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“PHARMACEUTICAL COMPOSITION FOR INHALATION COMPRISING LONG ACTING MUSCARINIC ANTAGONISTS AND LONG-ACTING ß-ADRENOCEPTOR AGONISTS”

We, ZYDUS LIFESCIENCES LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Corporate Park, Scheme No. 63, Survey No. 536, Khoraj (Gandhinagar), Near Vaishnodevi Circle, S. G. Highway, Ahmedabad – 382481, Gujarat, India,

The following specification particularly describes the invention and the manner in which it is to be performed:

PHARMACEUTICAL COMPOSITION FOR INHALATION COMPRISING LONG ACTING MUSCARINIC ANTAGONISTS AND LONG-ACTING ß-ADRENOCEPTOR AGONISTS

FIELD OF THE INVENTION
The present invention provides a pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator and one or more pharmaceutically acceptable excipients. The invention also relates to the process of preparing pharmaceutical composition for inhalation and use of pharmaceutical compositions for inhalation in the treatment of respiratory condition selected from asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airways diseases.

BACKGROUND OF THE INVENTION:
Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that is increasing its prevalence worldwide. In India, the estimated prevalence is about 12.36 million. It is currently the fourth leading cause of death in the UK & US, and predicted to rank third in the global impact of disease by the year 2020.

COPD is a preventable and treatable disease state characterized by air flow limitation that is not fully reversible. The airflow obstruction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs it also produces significant systemic consequences. COPD is associated with mucus hyper secretion, emphysema, and bronchiolitis.

The major goals of COPD therapy include relief of symptoms, improvement in physiological functions and limiting complications, such as abnormal gas exchange and exacerbation of disease. However, an integrated approach to the treatment of COPD involves a combination of healthcare maintenance such as smoking cessation, avoidance of indoor as well as outdoor pollutants, avoidance of occupational exposure to allergens, use of drugs and supplemental therapies in a step-wise fashion as the disease progresses.

With respect to the treatment of COPD, inhalation drug delivery has been used for many years for the delivery of pharmacologically active agents. Traditional asthma therapy with bronchodilators, steroids, mast cell stabilizers, and anticholinergic drugs has primarily used the pressurized metered-dose inhaler (MDI) as drug delivery system.

The pharmaceutically active agents present in formulations used in MDIs are either dissolved or suspended in a liquefied propellant gas. Most pharmaceutically active agents are not sufficiently soluble in pure propellants, either HFAs or CFCs. For simple two component formulations of active agent and propellant to be practical, active agent should be soluble or uniformly dispersible in the propellant. Therefore, through the incorporation of a co-solvent such as ethanol, many active agents can be dissolved in the resulting formulation. Hence, formulations in which the active agent is in a micronized or particulate form and are suspended in the propellant are generally preferred and more common. There are several reasons for this. It is important to control the size of the particles or droplets in the aerosol spray produced by a pMDI, or like device. For example, if the particles or droplets are to penetrate deep into the lungs, they should have a mass median aerodynamic diameter (MMAD) of less than 5µm. Controlling the size of the particles in an aerosol spray produced from a purely liquid formulation is more difficult than it is with a formulation comprising a suspended solid particulate pharmaceutically active agent. In the former case, many environmentally influenced factors, such as solvent evaporation rates have an effect on particle size. Further, the size of the particles produced by a suspension formulation is determined largely by the size of the active agent particles employed in its preparation, and this is a parameter that can be effectively controlled.

A second, but important, reason for suspension formulations being preferred is that many pharmaceutically active agents are chemically more stable as solids than they are when in solution formulations. For example, most pharmaceutically active compounds are much more susceptible to degradation by acid or alkali when in solution than they are when solid. It is also simply impossible to render many pharmaceutically active agents sufficiently soluble in a pharmaceutically acceptable propellant system, for a solution formulation to be a realistic option for them.

Further, the reason for suspension formulations being preferred to solutions is that solution formulations may be restricted by the drug loading capacity of the solvent. Drug loading levels will vary depending on the solvent and solute used, however, suspension systems are not limited in this way and routinely allow higher drug loads to be incorporated into the formulations.

Currently, there are several recommended classes of therapy for respiratory diseases, of which long acting muscarinic antagonist alone or in combination with long-acting ß-adrenoceptor agonists (LABAs), short acting ß-2 agonists, corticosteroids are the mainstay of symptom management in mild and moderate conditions.

Glycopyrronium bromide is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethyl- pyrrolidinium bromide but also known as glycopyrrolate. It is a long acting muscarinic antagonist that is currently administered by injection to reduce secretions during anaesthesia, taken orally to treat gastric ulcers and given in dry powder inhaler as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). It can be prepared using the procedure described in United States patent U.S. Patent no. 2,956,062.

Formoterol, whose chemical name is (±) N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide, is a highly potent and ß2 -selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. Formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers; (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R), which are diastereomers. Formoterol is available commercially only as a racemic diastereomer, (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this enantiomeric mixture. The racemic mixture that is commercially available for administration is a dihydrate of the fumarate salt. Formoterol was first disclosed in the U.S. Patent No. 3,994,974.

Vilanterol is a LABA with a 24-hour duration of action that is used for the preparation of a medicament in the prophylaxis and treatment of respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), respiratory tract infection and upper respiratory tract disease. It is also known with the chemical name of 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol of fomula given below:

The compound (I) and pharmaceutically acceptable salts thereof, in particular the acetate, triphenylacetate, a-phenylcinnamate, 1 -naphthoate and (R)-mandelate salts, are specifically described in WO03/024439A1 as well as the preparation method of the compound I.

Vilanterol is preferably administrated by inhalation, in fixed combination with fluticasone propionate, using the inhaler Breo Ellipta® that delivers powdered vilanterol/fluticasone from foil- wrapped blisters. It is also administrated by inhalation in fixed combination with umeclidinium bromide using the inhaler Anoro Ellipta® that delivers powdered vilanterol/umeclidinium from foil-wrapped blisters. Vilanterol is also available as TRELEGY ELLIPTA® as once-daily 'closed' triple therapy of an inhaled corticosteroids/long-acting beta-2 -agonists/long-acting muscarinic antagonist combination (fluticasone furoate/umeclidinium bromide/vilanterol trifenatate in a single device), with the aim of providing a new treatment option for the management of asthma by improving lung function, health-related quality of life and symptom control over established combination therapies.

Further, to assist better patient compliance, combination products are still needed. It would be highly desirable, however, to provide a combination therapy suitable to reduce bronchial inflammation, bronchial constriction and bronchial secretions in a single product or dosage form. It would also be desirable to provide such a combination product or composition in a form whereby the correct dosage of the various components is easily and safely administered.

U.S. Patent No. 8,313,732 describes pharmaceutical formulations comprising an active ingredient selected from the group consisting of formoterol, a stereoisomer and a physiologically acceptable salt of formoterol, in a solution of a liquefied HFA propellant along with ethanol and hydrochloric acid

US Patent No. 8,420,060 discloses a pharmaceutical aerosol formulation, comprising:
formoterol fumarate dehydrate and beclomethasone dipropionate; 2.0 to 4.8% w/w ethanol; HFA 134a; wherein said HFA134a is the sole propellant and said formoterol fumarate dihydrate is suspended in a micronized form in said formulation while said beclometasone dipropionate is fully dissolved.

US Patent No. 8,324,266 discloses methods and systems for pulmonary or nasal delivery of two or more active agents i.e. Glycopyrronium and Formoterol via a metered dose inhaler in which the compositions include a suspension medium, active agent particles, and plurality of suspending particles wherein the plurality of suspending particles are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium.

US Patent No. 7,759,328 discloses a pharmaceutical composition comprising formoterol fumarate dihydrate, budesonide, 1,1,1,2,3,3,3-heptafluoropropane (HFA227), PVP K25 (polyvinyl pyrrolidone with a nominal K-value of 25), and PEG-1000 (polyethylene glycol with an average molecular weight of 1,000), wherein the formoterol fumarate dihydrate is present at a concentration of 0.09 mg/ml, the budesonide is present at a concentration in the range of 1 mg/ml to 8 mg/ml, the PVP K25 is present at a concentration of 0.001% w/w, and the PEG-1000 is present at a concentration of 0.3% w/w.

PCT Publication No. WO 2010097114 discloses novel combinations of a muscarinic acetylcholine receptor antagonist and a beta-2 agonist for inhaled administration via the nose or mouth, and methods of using them are provided. Particularly, discloses combination of Vilanterol and Umeclidinium for use in the treatment and/or prophylaxis of inflammatory or respiratory tract diseases, such as chronic obstructive pulmonary disease (COPD) and/or asthma.

Combinations of Glycopyrronium and Formoterol are known in the art; see for example PCT Publication No. WO2010138884 discloses such a combination that is now marketed as Bevespi Aerosphere® in a pressurized metered dose inhaler. Formulations for pMDIs may require certain excipients as disclosed in PCT Publication No. WO2010138884. The formulation comprises a plurality of respirable suspending particles, the plurality of suspending particles are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium. However, in such kind of formulations the purity is difficult to control, and the nature is relatively unstable which can be metabolized to lysophospholipids in the process of usage and storage. Hence, it has shown to correlate with toxicity in animal models. Phospholipids are also prone to aggregation and hence phospholipid as a suspending agent may lead to physicochemical instability in MDIs.

Hence, there is an unmet need to provide stable suspension formulations comprising a pharmaceutically active agent for delivery using a spray or aerosol device, such as a pressurized metered dose inhaler (pMDI). In particular, it is desirable for the active agent within the suspension formulations to be stable, so that the physical and chemical state of the active agent is retained when the formulation is made and over time as it is stored and used. More specifically, it is also an aim of the present invention to provide a suspension formulation in which the suspension itself is physically stable, in that it exhibits a reduced tendency to flocculate and/or for the suspended particles to sediment and provide suspension formulations with a long shelf-life.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator and one or more pharmaceutically acceptable excipients, wherein the stabilizing modulator is a polymer or mixture of one or more polymers.

In one another aspect, the present invention provides a pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the compositions achieves desirable delivered dose uniformity (“DDU”) for multiple active agents, wherein at least one of the active agents to be delivered may be highly potent.

In one aspect, the present invention provides a pressurized meter dose pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the composition exhibits an emitted dose and lung deposition that is substantially independent of device resistance.

In yet another aspect, there is provided a pressurized meter dose pharmaceutical composition for inhalation comprising glycopyrronium or a salt thereof, formoterol or a salt thereof, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the composition exhibits an emitted dose and lung deposition that is substantially independent of device resistance.

In one preferred aspect, the present invention provides a pressurized meter dose pharmaceutical composition for inhalation comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, a stabilizing modulator, a carrier and one or more pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides a process of preparing a pressurized meter dose inhaler pharmaceutical composition comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein process comprising following steps:
1) mixing and homogenizing the stabilizing modulator with propellant for 30 minutes at 1000 RPM,
2) dividing the carrier particles into two equal parts,
3) geometrically mixing the micronized long-acting ß-adrenoceptor with one part of carrier and the micronized long acting muscarinic antagonist with another part of the carrier,
4) geometrically mixing both the parts from step 3) and blending for 30 minutes at 18 RPM,
5) adding the blend of step 4) into the mixture of step 1) and homogenized for 30 minutes at 1000 RPM, and
6) stirring and recirculating the blend of step 5) for 30 minutes and filling into the pre-crimped canisters.

In another general aspect, there is provided a method for the prophylaxis or treatment of inflammatory or obstructive diseases of the upper or lower respiratory tract, including asthma and chronic obstructive pulmonary diseases (COPD), and complications thereof such as pulmonary hypertension, comprising administering to said subject a pressurized meter dose inhaler pharmaceutical composition comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the stabilizing modulator is a polymer or mixture of one or more polymers.

DETAILED DESCRIPTION OF THE INVENTION:
Metered dose inhaler (MDI) compositions tend to flocculate and do have a potential for physical instability. The physical stability (particle size growth, flocculation rate, sedimentation/creaming behaviors) of a non-aqueous based suspension metered dose inhaler formulation is a critical factor that affects the pharmaceutical performance characteristics of the drug product. For a suspension MDI, the key pharmaceutical performance characteristics of the formulation include reproducible dosing, ready dispersibility of the suspended medicament, and minimal particle size change over time.

A further problem that is often associated with known formulations for delivery using devices such as pMDIs is their stability and consequently their shelf life. This especially applies to ethanol-free suspension formulations. These formulations and the pMDI products have a reduced shelf life due to moisture ingress. Generally, when the formulations are prepared they are free of moisture. However, once opened from their foil packaging, the shelf life of the pMDI formulation is dramatically reduced due to the ingress of moisture. The ingress of moisture can change the suspension characteristics, often leading to increased flocculation rate which leads to poor product performance and poor drug delivery.

Formulating pharmaceutical composition incorporating two or more active agents is often challenging due to unpredictable or unexpected interactions between the active agents or changes to the formulations resulting from the incorporation of multiple active agents. Such interactions are generally known as a “combination effect,” and in the context of suspension formulations delivered from an MDI, a combination effect may be manifest by, for example, a deviation from similarity between a formulation including a single active agent and a formulation including a combination of two or more active agents in one or more of the following areas: the aerosol and particle size distribution characteristics provided by the formulation; delivered dose uniformity for one or more of the active agents; deliverability or absorption of one or more of the active agents; or the dose proportionality observed for one or more of the active agents.

Hence, the inventors of the present invention have surprisingly found that effective dispersion of formulation with enhanced physical and chemical stability can be achieved by using suitable stabilizing modulator and the carrier. Moreover, addition of particular carrier with optimized concentration and ratio ensures uniformity of delivered doses of active pharmaceuticals with improved shelf life and better deposition of emitted doses into the lungs.

Therefore, in one of the embodiment, there is provided a pressurized meter dose inhaler pharmaceutical composition comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator and one or more pharmaceutically acceptable excipients, wherein the stabilizing modulator is a polymer or mixture of one or more polymers.

Stabilizing modulator suitable for use in the compositions described herein may be formed of one or more pharmaceutically acceptable materials or excipients that are suitable for inhaled delivery and do not substantially degrade or dissolve in the suspension medium. Stabilizing modulator includes synthetic or natural polymers or combinations thereof, but not limited to sorbitan esters including sorbitan trioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters, block copolymers include diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic™ F-68), poloxamer 407 (Pluronic™ F-127), and poloxamer 338. Ionic surfactants such as sodium sulfosuccinate, and fatty acid, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate, polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, celluloses, polyvinyl alcohols, polyanhydrides, polylactams, and hyaluronic acid.

The polymer may be a homopolymer, that is the polymer consists of the same recurring structural units, or it may be a co-polymer, that is the polymer contains recurring units that are not the same.

Preferred polymers include recurring structural units containing an amide group. In general, it has been found that polyvinylpyrrolidones having a wide range of average molecular weights give excellent aerosol pharmaceutical compositions, in particular suspensions. Particularly preferred embodiments of the invention are when the stabilizing polymer is polyvinylpyrrolidone (PVP), also known as povidone. Different types of PVP may be characterized by their viscosity in solution, expressed as a K-value (see European Pharmacopoeia, 5th ed., 2004, vol. 2, page 2289). Preferably the K-value of the PVP used is between 10 and 150, more preferably between 15 and 80, most preferably between 20 and 40, Suitable polyvinylpyrrolidones are PVP(K25), PVP(K30), Povidone K30, PVP(K29/32), PVP(K90), PVP(K120), PVP(C15), PVP(C30) or PVP/17PF.

Alternatively, the polymer may be Polyethylene glycol (PEG) or derivatives thereof or a co-polymer of vinyl acetate and vinyl pyrrolidone.

As used herein, a PEG derivative is a compound comprising one or more -(CH2CH2O)n- recurring units, wherein n is an integer = 2. Preferably n is = 4, = 6 or = 8. In one embodiment, n is = 20. Preferred PEG derivatives are linear. Most preferably the PEG derivative is polyethylene glycol (PEG), i.e. HO-(CH2CH2O)n-H. Preferably the average molecular weight of the PEG or PEG derivative is 50 to 1000 Da, more preferably 100 to 500 Da, most preferably 500 to 1000 Da.

Preferably, stabilizing modulator in the composition is the combination of polyethylene glycol and polyvinylpyrrolidone.

The amount of polymer in the composition will depend on the active ingredient to be dispersed, the concentration of the active ingredient and the particular polymer selected. However, in general the amount of polymer is from 0.00001 to 10% w/w, more preferably 0.0001 to 5% w/w and most preferably 0.0001 to 1% w/w.

In preferred embodiment, for guaranteeing that all doses released from the device contain a correct amount of active agent, the metered dose inhaler (MDI) devices should have consistent dose uniformity. It is quite important that the dose released from the metered dose inhaler device is the same every time, irrespective of the inhalation ability of the patient. For this reason, using carrier with correct properties in the composition helps in administering the dose in a consistent manner.

Small drug particles tend to agglomerate. This agglomeration can be prevented using suitable carrier or carrier mixtures. Additionally, they help in controlling the flowability of the drug being released from the device and providing a correct and consistent dosage of the active agent delivered to the lungs.

In addition, the mixture by which the drug particles bind to the carrier should be homogeneous. This binding, however, should not be too strong as the drug would not be released from the carrier particle during inhalation. One of the main parameters for the composition is the particle size of the carrier. For this reason, using a correct proportion of fine or coarse particles of the carrier selected for the compositions according to the present invention was found to be of great importance. In order to fulfill these requirements, inhalable fine or microfine particles of active agents are mixed with carriers.

For instance, the particle size and particle shape of the components in the composition directly influence the volume.

Therefore, there is provided a pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the compositions achieves desirable delivered dose uniformity (“DDU”) for multiple active agents, wherein at least one of the active agents to be delivered may be highly potent and the delivered doses of each of the active agents vary considerably.

Preferred carrier include but are not limited to (a) carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as sucrose, lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-ß- cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, starches, chitin, chitosan, inulin, and the like; (b) amino acids, such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine, and the like; (c) metal and organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins such as aspartame, leucine, human serum albumin, collagen, gelatin, and the like; (e) alditols, such as mannitol, xylitol, and the like; (f) synthetic or natural polymers or combinations thereof, such as polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, hyaluronic acid, polyethylene glycols; and (g) surfactants including fluorinated and nonfluorinated compounds such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof. In particular embodiments, carrier may include a calcium salt, such as calcium chloride, as described, for example, in U.S. Patent No. 7,442,388.

Preferably, carrier in the composition is lactose or lactose monohydrate.

The carrier may be reduced to the required particle size by any convenient method, e.g. grinding, air-jet milling, ball milling and the like.

Further, it was surprisingly found that aerosol composition can be prepared by introducing a carrier having a mass median diameter of less than 10 micron, more preferably less than 5 micron. Moreover, the carrier with optimized ratio with active pharmaceuticals was readily re-dispersible and avoiding invariability dosing of the drug and enhanced the deposition of emitted dose into the lungs.

Therefore, there is provided a pharmaceutical composition for inhalation comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the composition exhibits an emitted dose and lung deposition that is substantially independent of device resistance and inspiratory effort, respectively.

In preferred embodiment, the weight ratio of drug to carrier is in the range 1:0.1 to 1:10, more preferably 1:0.5 to 1:8, most preferably 1:0.5 to 1:5.

In certain embodiments, the long acting muscarinic antagonist may be selected from, for example, glycopyrrolate or glycopyrronium, dexpirronium, tiotropium, trospium, aclidinium, darotropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

In preferred embodiments, the long acting muscarinic antagonist included in the compositions described herein is glycopyrrolate or glycopyrronium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

Glycopyrrolate or glycopyrronium or a salt thereof can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein. As an anticholinergic, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect, which is a benefit for use in the therapy of pulmonary diseases and disorders characterized by increased mucus secretions. Glycopyrrolate is a quaternary ammonium salt. Where appropriate, glycopyrrolate may be used in the form of salts (e.g. alkali metal or amine salts, or as acid addition salts) or as esters or as solvates (hydrates). Additionally, the glycopyrrolate may be in any crystalline form or isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. In this regard, the form of glycopyrrolate may be selected to optimize the activity and/or stability of glycopyrrolate and/or to minimize the solubility of glycopyrrolate in the suspension medium. Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. In particular embodiments of the compositions described herein, the bromide salt of glycopyrrolate, namely 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, is used and can be prepared according to the procedures set out in U.S. Patent No. 2,956,062.

According to the present invention, glycopyrrolate or glycopyrronium or a salt thereof may be present in an amount of from about 5mcg to about 200mcg.

In certain embodiments, the compositions described herein include a LABA active agent. In such embodiments, a LABA active agent can be selected from, for example, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, vilanterol, olodaterol and saligenin- or indole- containing and adamantyl-derived ß2 agonists, and pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain such embodiments, formoterol is selected as the LABA active agent. Formoterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as, for example, those described herein. Formoterol has the chemical name (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1-RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl] formanilide, and is commonly used in pharmaceutical compositions as the racemic fumarate dihydrate salt. Where appropriate, formoterol may be used in the form of salts (e.g. alkali metal or amine salts or as acid addition salts) or as esters or as solvates (hydrates). Additionally, the formoterol may be in any crystalline form or isomeric form or mixture of isomeric forms, for example a pure enantiomer, a mixture of enantiomers, a racemate or a mixture thereof. In this regard, the form of formoterol may be selected to optimize the activity and/or stability of formoterol and/or to minimize the solubility of formoterol in the suspension medium. Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p- methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids. Hydrates of formoterol are described, for example, in U.S. Patent No. 3,994,974 and U.S. Patent No. 5,684,199. Specific crystalline forms of formoterol and other ß2 adrenergic receptor agonists are described, for example, in PCT Publication No. WO 95/05805, and specific isomers of formoterol are described in U.S. Patent No. 6,040,344. In specific embodiments, the formoterol material utilized to form the formoterol particles is formoterol fumarate, and in one such embodiment, the formoterol fumarate is present in the dihydrate form. Where the compositions described herein include formoterol, in certain embodiments, the compositions described herein may include formoterol at a concentration that achieves a targeted delivered dose selected from between about 1 µg and about 30 µg, about 1 µg and about 10 µg, about 2 µg and 5 µg, about 2 µg and about 10 µg, about 5 µg and about 10 µg, and 3 µg and about 30 µg per actuation of an MDI. In other embodiments, the compositions described herein may include formoterol in an amount sufficient to provide a targeted delivered dose selected from up to about 30 µg, up to about 10 µg, up to about 5 µg, up to about 2.5 µg, up to about 2 µg, or up to about 1.5 µg per actuation.

The pharmaceutical composition of the invention comprises vilanterol or a salt thereof as an active agent. Vilanterol can be in the form of free base or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, preferably in the form of a salt, in the formulation. Pharmaceutically acceptable salts of vilanterol according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutical acceptable acid addition salts of vilanterol include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, phenylacetic, substituted phenyl acetic e.g. methoxyphenyl acetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulponic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, mandelic, cinnamic, substituted cinnamic (for example, methyl, methoxy, halo or phenyl substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid and a-phenyl cinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1-or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, bezeneacrylic (for example 1,4 benzenediacrylic) and isethionic acids. Pharmaceutical acceptable base salts of vilanterol include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.

In one embodiment of the present invention, vilanterol triphenylacetate is preferably used in as active agent in the present pharmaceutical composition.

Vilanterol or a salt thereof is preferably present in an amount of 0.05 - 2.5%, more preferably present in an amount of 0.05 -1.5%, most preferably present in an amount of 0.1 -1.0 % by weight of the total formulation wherein the weight of vilanterol or a salt thereof is calculated as the free base.

In one preferred embodiment, active ingredients are in micronized form.

In one preferred embodiment, there is provided a pressurized meter dose inhaler pharmaceutical composition comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, a stabilizing modulator, a carrier and one or more pharmaceutically acceptable excipients.

In one preferred embodiment, there is provided a a pressurized meter dose inhaler pharmaceutical composition comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, a stabilizing modulator, a carrier and one or more pharmaceutically acceptable excipients, wherein the composition when stored at 40°C/75% RH is stable for at least one month.

In one preferred embodiment, there is provided a pressurized meter dose inhaler pharmaceutical composition comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, a stabilizing modulator, a carrier and one or more pharmaceutically acceptable excipients, wherein the composition when stored at 40°C/75% RH is stable for at least three month.

Pharmaceutically acceptable excipients include but not limited to propellants, preservatives, antioxidants, chelating agents, buffers, sweeteners, taste masking agents and like.

Examples of the suitable propellants for the composition according to the invention may be selected from, but not limited to hydrocarbons, volatile ethers and/or hydrofluoroalkanes. Hydrofluoroalkanes can be selected from the group: Norflurane (1,1,1,2-Tetrafluoroethane, also called HFA 134a), HFA 227ea (1,1,1,2,3,3,3-heptafluoropropane) or others known in the art. Hydrocarbons can be selected from the group: isobutane, propane, n-butane, n-pentane or others known in the art.

Examples of the suitable preservatives for the composition according to the invention may be selected from, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate and phenyl ethyl alcohol. The amount of the preservative present in the pharmaceutical composition may range from about 0.005 to about 1% w/w relative to the total weight of the composition.

Examples of suitable antioxidants for the composition according to the invention may be selected from, but not limited to ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione and the like. The amount of the antioxidant present in the pharmaceutical composition may ranges from about 0.0002 to about 0.5% w/w relative to the total weight of the composition.

Examples of suitable chelating agents for the composition according to the invention may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA. The amount of the chelating agent present in the pharmaceutical composition may range from about 0.0001 to1% w/w relative to the total weight of the composition.

Examples of suitable buffers may include one or more of borate buffers, tartrate buffers, lactate buffers, citrate buffers, phosphate buffers (e.g. potassium phosphate monobasic), citric acid/phosphate buffers, carbonate/carbonic acid buffers, succinate/succinic acid buffers, and tris(hydroxymethyl)aminomethane /hydrochloric acid buffers and the like. The amount of aqueous solvent and co-solvent may range from about 0.005% w/w to about 1% w/w of the composition.

Examples of suitable sweetener/taste masking agents may be selected from, but not limited to sucralose. thaumatin (e.g., Talin®) sucrose, saccharin (including the salt forms: sodium, calcium, etc.), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents.

In one embodiment, the compositions of the present invention may further comprise an inhaled corticosteroid.

In yet another embodiment, the present invention provides a process of preparing a pressurized meter dose inhaler pharmaceutical composition comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein process comprising following steps:
1) mixing and homogenizing the stabilizing modulator with propellant for 30 minutes at 1000 RPM,
2) dividing the carrier particles into two equal parts,
3) geometrically mixing the micronized long-acting ß-adrenoceptor with one part of carrier and the micronized long acting muscarinic antagonist with another part of the carrier,
4) geometrically mixing both the parts from step 3) and blending for 30 minutes at 18 RPM,
5) adding the blend of step 4) into the mixture of step 1) and homogenized for 30 minutes at 1000 RPM, and
6) stirring and recirculating the blend of step 5) for 30 minutes and filling into the pre-crimped canisters.

In yet another embodiment, the present invention provides a process of preparing a pressurized meter dose inhaler pharmaceutical composition comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein process comprising following steps:
1) mixing and homogenizing the stabilizing modulator with propellant for 30 minutes at 1000 RPM,
2) dividing the carrier particles into two equal parts,
3) geometrically mixing the vilanterol or a salt thereof with one part of carrier and the glycopyrronim or a salt thereof with another part of the carrier,
4) geometrically mixing both the parts from step 3) and blending for 30 minutes at 18 RPM,
5) adding the blend of step 4) into the mixture of step 1) and homogenized for 30 minutes at 1000 RPM, and
6) stirring and recirculating the blend of step 5) for 30 minutes and filling into the pre-crimped canisters.

In another embodiment, there is provided a method for the prophylaxis or treatment of inflammatory or obstructive diseases of the upper or lower respiratory tract, including asthma and chronic obstructive pulmonary diseases (COPD), and complications thereof such as pulmonary hypertension, comprising administering to said subject a pressurized meter dose inhaler pharmaceutical composition comprising at least one long acting muscarinic antagonist, at least one long-acting ß-adrenoceptor agonist, stabilizing modulator, carrier and one or more pharmaceutically acceptable excipients, wherein the stabilizing modulator is a polymer or mixture of one or more polymers.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

Example-1:
Sr.
No. Name of Ingredient % w/w
1 Glycopyrrolate (Micronized) 0.0146
2 Formoterol Fumarate Dihydrate (Micronized) 0.0077
3 Polyethylene Glycol 1000 0.0183
4 Polyvinyloyrrolidone K25 0.0001
5 Lactose monohydrate (Micronized) 0.1392
6 Hydrofluoroalkanes (HFA 227ea) 99.8201
Total 100.00

Process of Preparation:
1) Polyethylene glycol 1000 and polyvinyloyrrolidone K25 were mixed and homogenized with hydrofluoroalkanes for 30 minutes at 1000 RPM,
2) micronized lactose monohydrate was divided into two equal parts,
3) micronized formoterol fumarate dihydrate was geometrically mixed with one part of lactose monohydrate,
4) micronized glycopyrrolate was mixed with another part of lactose monohydrate,
5) mixtures of step 3) and step 4) were geometrically mixed and blended for 30 minutes at 18 RPM,
6) blend of step 5) was mixed and blended with the mixture of step 1) at 1000 RPM for 30 minutes, and
7) the blend of step 6) was stirred with recirculated for 30 minutes and filled into the pre-crimped canisters.

Stability data:
Content of active ingredient delivered per actuation
(X-Valve)
Initial 1 M
40°C/75% RH 3 M
40°C/75% RH
Glycopyrrolate
(%LC) Formoterol fumarate
(%LC) Glycopyrrolate
(%LC) Formoterol fumarate
(%LC) Glycopyrrolate
(%LC) Formoterol fumarate
(%LC)
Mean 104.2 99.5 102.2 100.7 104.3 105.1

Example-2
Objective: Study to evaluate the uniformity of delivered dose
Method:
1. Connect the suitable pump to the outlet of the DUSA apparatus. Adjust the airflow through the apparatus to 28.3±5% liter/minute.
2. Fit the canister in actuator. Remove the flow meter from the DUSA. Locate the canister with actuator into the DUSA tube, fix it to the assembly with the help of mouthpiece adaptor and fire one shot immediately. Keep the valve depressed for one second.
3. Switch off the pump.
4. Remove the canister with actuator and mouthpiece from DUSA apparatus. Place the screw cap on the adaptor side of the DUSA tube.
5. Remove the DUSA tube from the clamp and close it from filter holder side with another screw cap.
6. Add the diluent into the DUSA tube and collect and filter the sample solution.
7. Above mentioned steps to be repeated for additional 9 analysis of beginning, middle and end samples.

Results:

Uniformity of Delivered dose (Ex Actuator)
Initial 1 M
40°C/75% RH 3 M
40°C/75% RH
(3,4,3) Glycopyrrolate Formoterol Fumarate Glycopyrrolate Formoterol Fumarate Glycopyrrolate Formoterol Fumarate
Mean 94.0 95.2 97.8 97.0 93.8 95.7
Min 82.7 86.3 86.7 88.3 90.7 93.3
Max 112.1 106.9 107.4 105.8 96.8 97.5

Example-3:
Objective: Comparative analysis of deposition of emitted dose (%T2) with the commercial product
Method:
1. Arrange the glass Impinger assembly and add the diluent in upper impinger chamber and in lower impinger chamber. Connect all the component parts.
2. Without the inhaler in place, connect the suitable pump to the outlet of the apparatus. Adjust the airflow through the apparatus to 60±5% ltr./min.
3. Switch off the pump and attach the mouthpiece adaptor to the throat of the assembly, fit the canister in its actuator. Switch on the pump and deliver 10 actuation inside the assembly. Shaking for at least 5 seconds in between each actuation.
4. Wash the upper impinger (T1) and lower impinger (T2) with suitable diluent and analyze with HPLC further.

Results:
Deposition of emitted dose (%T2)
Life stage Initial 1 M
40°C/75% RH 3 M
40°C/75% RH
Glycopyrrolate Formoterol Fumarate Glycopyrrolate Formoterol Fumarate Glycopyrrolate Formoterol Fumarate
T2 40.03 59.44 44.1 55.93 42.79 58.46
MB 95.96 95.28 99.14 98.36 91.11 89.20

Example-4:
Sr.
No. Name of Ingredient Qty per act
(mcl)
1 Glycopyrrolate (Micronized) 0.0104
2 Formoterol Fumarate Dihydrate (Micronized) 0.0055
3 Polyethylene Glycol 1000 0.0119
4 Polyvinyloyrrolidone K25 0.00015
5 Lactose monohydrate (Micronized) 0.0994
6 Hydrofluoroalkanes (HFA 227ea) 49.8730

Process of Preparation:
1) Polyethylene glycol 1000 and polyvinyloyrrolidone K25 were mixed and homogenized with hydrofluoroalkanes for 30 minutes at 1000 RPM,
2) micronized lactose monohydrate was divided into two equal parts,
3) micronized formoterol fumarate dihydrate was geometrically mixed with one part of lactose monohydrate,
4) micronized glycopyrrolate was mixed with another part of lactose monohydrate,
5) mixtures of step 3) and step 4) were geometrically mixed and blended for 30 minutes at 18 RPM,
6) blend of step 5) was mixed and blended with the mixture of step 1) at 1000 RPM for 30 minutes, and
7) the blend of step 6) was stirred with recirculated for 30 minutes and filled into the pre-crimped canisters.

Stability data:
S. No. Test Specification Initial 1 M 3 M 6 M
1 Description Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve
2 Content of active ingredient delivered per actuation 80-120% of Label Claim Glycopyrrolate 102.6 99.2 105.9 98.3
Formoterol Fumarate 107.6 95.9 105.5 95.3
3 Aerodynamic Assessment of Fine Particles (APSD using Twin Impinger) % T2 values NLT 25% of Label Claim Glycopyrrolate 54.04 42.39 54.04 51.61
Formoterol Fumarate 67.6 54.56 63.11 57.64
4 Uniformity of Delivered Dose Not More than one of the individual values of the 10 determinations tested is outside the limits 75 % to 125 % of the average value and none is outside the limits of 65% and 135%.
If two or three values lie outside the limits of 75% to 125%, repeat the test for two more inhalers.
Not More than 3 of the 30 values lie outside the limits 75 % to 125 % and no value lies outside the limits of 65 % to 135 % of the average value. Glycopyrrolate 91.3 – 106.1 86.6 – 116.9 74.7 – 124.7 86.8 – 110.2
Formoterol Fumarate 92.3 – 105.9 84.5 – 117.5 80.5 – 121.0 88.1 – 109.0
5 Water Content NMT 1500 ppm 422 369 429 354
6 Impurities and degradation products Max individual unknown degradation product BQL BQL BQL 0.1
Total degradation product BQL BQL BQL 0.16

Example 5: Vilanterol and Glycopyrrolate composition
Sr. No. Name of Ingredients %W/W
1 Vilanterol Trifenatate 0.036
2 Glycopyrrolate IP (Micronized) 0.057
3 Lactose Monohydrate NF (INHALAC 500) 0.091
4 MACROGOL PH.EUR. (PEG) 0.01
5 HFA 134a 99.806
Total 100

Process of Preparation:
1) Polyethylene glycol 1000 and polyvinyloyrrolidone K25 were mixed and homogenized with hydrofluoroalkanes for 30 minutes at 1000 RPM,
2) micronized lactose monohydrate was divided into two equal parts,
3) micronized vilanterol trifenatate was geometrically mixed with one part of lactose monohydrate,
4) micronized glycopyrrolate was mixed with another part of lactose monohydrate,
5) mixtures of step 3) and step 4) were geometrically mixed and blended for 30 minutes at 18 RPM,
6) blend of step 5) was mixed and blended with the mixture of step 1) at 1000 RPM for 30 minutes, and
7) the blend of step 6) was stirred with recirculated for 30 minutes and filled into the pre-crimped canisters.

The stability results for Vilanterol and Glycopyrrolate composition when stored at accelerated conditions at 40°C/75%RH is provided in the table below.
Stability data for Vilanterol and Glycopyrrolate composition
S. No. Test Specification Active Initial 1 M
1 Description Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve Pressurized metered dose inhaler containing suspension filled in aluminium canister fitted with metered valve
2 Content of active ingredient delivered per actuation 80-120% of Label Claim Vilanterol 107.8 109.3
Glycopyrrolate 106.2 112.1
3 Uniformity of Delivered Dose
(on two actuations=1 dose) Not More than one of the individual values of the 10 determinations tested is outside the limits 75 % to 125 % of the average value and none is outside the limits of 65% and 135%.

Vilanterol 89.9-107 80-96.7
Glycopyrrolate 88.9-106 83.7-100.3
% Average Value Vilanterol
91-108.3 89.6-108.3
Glycopyrrolate
90.83-108.3 90-107.9
4 Water Content
NMT 1000 ppm
174 231
5 Impurities and degradation products Glycopyrrolate Impurity C: NMT 1% ND ND
Triphenylmethane: NMT 1% ND 0.12
Any unspecified degradation product : NMT 0.5% 0.16 0.17
Total degradation product: NMT 2 % 0.16 0.29

Deposition of the emitted dose for Vilanterol and Glycopyrrolate Composition
Deposition of emitted dose (%T2)
Life stage Initial 1 M
40°C/75% RH
Vilanterol Glycopyrrolate Vilanterol Glycopyrrolate
Canister No.. 1 2 3 1 2 3 1 2 3 1 2 3
T2 52 47.5 48.6 44.9 40.7 42.5 46.7 40.2 44.3 40.9 36.5 40.6
T1 54.5 62.6 59.8 62.7 70.4 65.8 51 50.6 51.8 61.1 59.4 60.5
, Claims:We claim:
1. A pressurized meter dose pharmaceutical composition for inhalation, wherein the composition comprises glycopyrronium or a salt thereof, vilanterol or a salt thereof, a stabilizing modulator, a carrier, and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition for inhalation as claimed in claim 1, wherein the stabilizing modulator is selected from polyvinylpyrrolidone, polyethylene glycol (PEG), or a combination thereof.

3. The pharmaceutical composition for inhalation as claimed in claim 1, wherein the carrier is lactose.

4. The pharmaceutical composition for inhalation as claimed in claim 1, wherein weight ratio of glycopyrronium or a salt thereof and vilanterol or a salt thereof to carrier is from 1:0.1 to 1:10.

5. The pharmaceutical composition for inhalation as claimed in claim 1, wherein the composition when stored at 40°C/75% RH is stable for at least one month.

6. The pharmaceutical composition for inhalation as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients comprise one or more of propellants, preservatives, antioxidants, chelating agents, buffers, sweeteners, and taste masking agents.

7. A process for the preparation of a pressurized meter dose inhaler pharmaceutical composition comprising glycopyrronium or a salt thereof, vilanterol or a salt thereof, stabilizing modulator, carrier, and one or more pharmaceutically acceptable excipients, the process comprising:
1) mixing and homogenizing the stabilizing modulator with a propellant for 30 minutes at 1000 RPM,
2) dividing the carrier particles into two equal parts,
3) geometrically mixing vilanterol or a salt thereof with one part of the carrier and glycopyrronium or a salt thereof with another part of the carrier,
4) geometrically mixing both the parts from step 3) and blending for 30 minutes at 18 RPM,
5) adding the blend of step 4) into the mixture of step 1) and homogenized for 30 minutes at 1000 RPM, and
6) stirring and recirculating the blend of step 5) for 30 minutes and filling into pre-crimped canisters.

Dated this the 14th day of June 2022.


GAYATRI BHASIN
(IN/PA-1246)
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS